This invention pertains to a delivery device for the controlled release of active agents to an environment of use. More particularly, the invention pertains to a device for the delivery of active agents over a prolonged and extended period of time. The controlled delivery device comprises an expandable-hydrophilic polymer-core located substantially in the center of the dosage form surrounded by a composition of the active agent(s) to be delivered. A novel dual function membrane permits delivery of the active agent(s) through a combination of diffusion and osmotic pumping mechanisms.
Osmotic devices have demonstrated utility in delivering beneficial active agents, such as medicines, nutrients, food, pesticides, herbicides, germicides, algaecides, chemical reagents, and others, to an environment of use in a controlled manner over prolonged periods of time. Known devices include tablets, pills, and capsules.
Several advancements have been made in the art to improve the delivery of insoluble or slightly soluble products to an environment of use. The prior art has focused on the development of new membranes that deliver active agents by diffusion and/or osmotic pumping.
U.S. Pat. No. 4,235,236 to Theeuwes discloses an osmotic device that delivers drug by the combined mechanisms of diffusion and osmotic pumping. The device comprises a microporous wall surrounding a compartment containing an active agent and an expandable member. The expandable member consists of a semipermeable, flexible or expandable film surrounding a member selected from the group consisting of an osmotically effective solute, a gas generating couple and a swellable polymer. The external wall of the device is formed of a microporous material through which the active agent is delivered. This patent does not disclose the inclusion of a passageway in the external wall to provide delivery by osmotic pumping and diffusion. Even though the solution proposed by U.S. Pat. No. 4,235,236 allows the release of an active agent at a steady ratexe2x80x94the so called zero-order releasexe2x80x94, it requires the manufacturing of an elastic film that separates the expandable member from the composition comprising the active agent. The adhesion process between said membrane and said composition comprising the active agent requires complicated processing steps that make the formulation very expensive.
U.S. Pat. No. 4,327,725 to Cortese and Theeuwes, discloses an osmotic device comprising a semipermeable wall surrounding two layers, one layer containing an active agent and the other an expandable hydrogel. A passageway in the wall communicates the active agent layer with the environment of use. The patent describes the use of cellulose acylate as the material comprising the semipermeable membrane.
U.S. Pat. Nos. 5,612,059 and 5,698,220 to Cardinal et al., disclose the use of asymmetric membranes in delivery devices. These membranes may be permeable, semipermeable, perforated or unperforated and can deliver an active substance by the combined mechanisms of diffusion and osmotic pumping. These patents also disclose the formation of asymmetric membranes with 398-10 (Eastman) cellulose acetate.
EP 636366 and EP 553392 disclose an active agent composition coated with an aqueous dispersion of plasticized acrylic polymer, which is subjected to a particular curing process. The controlled release formulation disclosed in these applications has a stable dissolution profile despite exposure to a variety of storage conditions.
U.S. Pat. No. 5,543,155 to Fekete et al. discloses a controlled delivery pharmaceutical composition core surrounded by a wall comprising an ammonium methacrylate copolymer that is permeable to low molecular weight (MW) molecules. This controlled delivery pharmaceutical composition contains an active pharmaceutical compound and hydroxypropyl methylcellulose (HPMC) as the hydrophilic polymer. Low MW osmagents are not incorporated into the composition. Tablets having a bi-layered core are prepared with a hydrophilic polymer layer comprising high molecular weight HPMC, which has a viscosity higher than 1000 cP in a 2% aqueous solution.
U.S. Pat. No. 5,543,155 also discloses various combinations of Eudragit(trademark) RL (easily permeable films) and Eudragit(trademark) RS (not easily permeable films). The use of a permeable membrane alone, however, does not allow the inclusion of a low molecular weight osmotic agent in the pharmaceutical composition tablet core (for example, potassium chloride, sodium tartrate, sodium chloride, sodium sulfate, etc.). Thus, it limits the versatility of the device to the delivery of active agents that require a significant absorption of liquid to achieve an effective and constant delivery of solution or suspension of the active agent from the device. Osmotic devices having a bi-layered core, one layer containing the active agent and the other being a swellable placebo layer, surrounded by a semipermeable membrane possess significant disadvantages. The placebo layer consists mainly of a swellable polymer and/or a hydrogel that, while absorbing fluid from the environment of use, expands and exerts pressure over the layer that contains the active agent thereby releasing the active agent through a passageway in the wall. The prior art teaches that perforation of the semipermeable membrane needs to be carried out selectively on the side of the membrane that is adjacent to the layer comprising the active agent. In fact, if the membrane is perforated adjacent the placebo layer, the active agent will not be released. If two perforations are carried out, one adjacent the active-agent layer and the other adjacent the swellable polymer layer (xe2x80x9cpushxe2x80x9d layer), both the active agent and the swellable polymer are released, resulting in loss of the xe2x80x9cpushxe2x80x9d effect. The device would therefore act as a simple osmotic pump that would not allow the release of the entire charge of active agent in the dosage form. The precise selection of which portion of the membrane should be drilled requires the use of color or shape coding in order to distinguish the layers, as well as meticulous handling of the devices. The handling of the devices requires the use of sophisticated and expensive electronic equipment able to recognize the different layers of the tablet core.
U.S. Pat. No. 5,543,155 also discloses perforation of the membrane adjacent both layers of the core; however, a specific high molecular weight polymer (HPMC) is required to prevent the loss of the push layer leaving a significant number of available hydrophilic polymers unavailable for use in these devices.
U.S. Pat. No. 5,516,527 to Curatolo discloses a device that can include a preformed passageway and plural pores. The device requires the formation of a phase-separated coating that ultimately forms a porous membrane.
While the prior art discloses a wide variety of osmotic devices, no single device has been found to be generally applicable and, in fact, most known devices are designed to operate within a relatively narrow range of conditions. For example, a first formulation of an osmotic device may be generally useful for delivering slightly to sparingly water soluble components to an environment of use, but that same formulation will require drastic changes in order to deliver a very water soluble component and vice versa. In addition, diffusion controlled devices are generally useful for delivering sparingly to very, but not slightly, water soluble components to an environment of use. Therefore, a need remains for a delivery device capable of delivering components having very different solubilities to an environment of use without requiring a dramatic reformulation of the device.
The present invention provides a controlled release device for active substances comprising an external dual delivery membrane having at least one preformed passageway and plural micropores, wherein the device releases the active agent through a combination of diffusion and osmotic pumping. The at least one passageway can be located anywhere in the dual delivery membrane.
The present invention also provides a controlled release device having an approximately centrally located core comprising a hydrophilic expandable polymer and, optionally, an osmagent, wherein the core is surrounded by a composition comprising at least one active agent and preferably an osmagent and/or an osmopolymer. During operation in an environment of use, the hydrophilic core imbibes fluid and increases in volume thereby forcing release of the active agent(s) through either the pores of the membrane by diffusion and/or the passageway by osmotic pumping effect.
The invention also provides a therapeutic device for the delivery of pharmaceutically active agents, ranging in solubility from slightly soluble to very soluble drugs, in a controlled, continuous and approximately steady, preferably zero order, rate over a prolonged period of time.
The invention also provides a smaller than usual dosage form that delivers active compounds by diffusion through the entire surface of the device. In this way, a portion of the membrane that releases active compounds is doubled with respect to conventional bi-layered devices.
The invention also provides a controlled release device containing a high or low molecular weight osmagent inside the core of the device, thereby enabling the device to absorb greater quantities of fluid, deliver a greater range of active agents irrespective of their solubility, and deliver the active agents by diffusion and/or osmotic pumping.
The device of the present invention may optionally be provided with an external coating comprising one or more active agents for immediate delivery to the environment of use.
Accordingly, one aspect of the present invention provides an improved device for the controlled delivery of active agents to an environment of use, wherein the device comprises:
a) a core located approximately at the center of the device and comprising at least one expandable hydrophilic polymer and optionally an osmagent, the core being able to absorb and/or imbibe fluids from one environment of use;
b) a composition immediately surrounding the core comprising at least one active substance and, optionally, an osmagent and/or an osmopolymer;
c) a membrane immediately surrounding the composition and comprising a mixture of a cellulose acylate (ester), a methacrylate salt copolymer and a plasticizer, wherein the membrane permits delivery of the at least one active substance through a combination of diffusion and osmotic pumping; and
d) at least one preformed passageway and plural micropores in the membrane that communicate the composition with the outside of the device.
Another aspect of the invention provides a device for the controlled delivery of at least one active agent to an environment of use, wherein the device comprises:
a core expandable in a fluid from the environment of use, the core being approximately centrally located in the device;
a layer comprising at least one first active agent, wherein the layer is in contact with and surrounds the core; and
a membrane in contact with and surrounding the layer and comprising at least one preformed passageway for delivery of the at least one active agent by osmotic pumping and plural micropores for delivery of the at least one active agent by diffusion, and the membrane further comprising one or more cellulose esters, one or more poly(methacrylate) copolymer salts and one or more plasticizers,
wherein the membrane permits delivery of the at least one active substance through a combination of diffusion and osmotic pumping.
Specific embodiments of the invention include those wherein: 1) the device further comprises a drug-containing coat external to the membrane, wherein the drug-containing coat comprises a second active agent, provides an immediate, rapid, controlled and/or delayed release of the second active agent and the external coat surrounds at least a portion of the membrane; 2) the first and second active agents are different and are independently selected at each occurrence from the group consisting of an antibiotic agent, antihistamine agent, decongestant, anti-inflammatory agent, antiparasitic agent, antiviral agent, local anesthetic, antifungal agent, amoebicidal agent, trichomonocidal agent, analgesic agent, anti-arthritic agent, anti-asthmatic agent, anticoagulant agent, anticonvulsant agent, antidepressant agent, antidiabetic agent, antineoplastic agent, anti-psychotic agent, neuroleptic agent, antihypertensive agent, hypnotic agent, sedative agent, anxiolytic energizer agent, antiparkinson agent, muscle relaxant agent, antimalarial agent, hormonal agent, contraceptive agent, sympathomimetic agent, hypoglycemic agent, antilipemic agent, ophthalmic agent, electrolytic agent, diagnostic agent, prokinetic agent, gastric acid secretion inhibitor agent, anti-ulcerant agent, anti-flatulent agent, anti-incontinence agent, and cardiovascular agent; 3) the first active agent is a prokinetic agent and the second active agent is a gastric acid secretion inhibitor agent; 4) the first active agent is a decongestant and the second active agent is an antihistamine; 5) the first active agent is a first anti-incontinence agent and the second active agent is a different second anti-incontinence agent; 6) the anti-incontinence agents are selected from the group consisting of oxybutynin, tolterodine and darifenacin; 7) the first active agent is a first antihypertensive agent and the second active agent is a different second antihypertensive agent; 8) the antihypertensive agents are selected from the group consisting of a calcium channel blocker agent, an angiotensin converting enzyme inhibitor agent, a diuretic agent and a beta-adrenergic antagonist agent; 9) the first active agent is an antidepressant agent and the second active agent is an anti-psychotic agent; 10) the first active agent is a first analgesic or, anti-inflammatory agent and the second active agent is a different second analgesic or, anti-inflammatory agent; 11) the analgesic and anti-inflammatory agents are selected from the group consisting of an non-steroidal anti-inflammatory agent, a steroidal anti-inflammatory agent, an opioid receptor agonist agent, and a selective or specific COX-II inhibitor agent; 12) the first active agent is an antiviral agent and the second active agent is an antihistamine agent; 13) the first active agent is a muscle relaxant agent and the second active agent is an anti-inflammatory or analgesic agent; 14) the first active agent is pridinol and the second active agent is a selective or specific COX-II inhibitor agent; 15) the first and second active agents are the same; 16) the membrane comprises about 1 to 99 weight percent of one or more cellulose esters, about 84 to 0.5 weight percent of one or more poly(methacrylate) copolymer salts and about 15 to 0.5 weight percent of one or more plasticizers; 17) the cellulose ester is selected form the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate and combinations thereof; 18) the poly(methacrylate) copolymer salt is poly(ammonium methacrylate) copolymer; 19) the layer further comprises at least one of an osmagent and an osmopolymer; the expandable core further comprises at least one expandable hydrophilic polymer and, optionally, an osmagent; 20) the expandable hydrophilic polymer is one or more of hydroxypropyl methylcellulose, alkylcellulose, hydroxyalkylcellulose, poly(alkylene oxide), and combinations thereof; and the at least one cellulose ester is independently selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate and combinations thereof; 21) the core excludes an active agent; 22) the membrane comprises a mixture of a cellulose acylate, a poly(methacrylate) copolymer salt and a plasticizer; 23) a slightly soluble or insoluble active substance is delivered predominantly through the at least one passageway and a soluble or sparingly soluble active substance is delivered predominantly through the plural micropores; and/or 24) the active substance is delivered at an approximately zero order rate.
Active agents can include compounds such as biologically or pharmacologically active agents, medicines, nutrients, food products, insecticides, pesticides, herbicides, germicides, algaecides, fungicides, chemical reagents, growth regulating substances, parasiticides, sex sterilants, fertility promoters, biocides, rodenticides, disinfectants, anti-oxidants, plant growth promoters, preservatives, fermentation agents, fertility inhibitors, deodorants, micro-organism attenuators, catalysts, food supplements, cosmetics, vitamins, and other agents that benefit the environment of use.
Preferred embodiments of the invention include those wherein the active substance is pharmacologically or biologically active or wherein the environment of use is the GI tract of a mammal.
Other preferred embodiments of the device of the invention are used in biological environments including the oral, ocular, nasal, vaginal, glandular, gastrointestinal tract, rectal, cervical, intrauterine, arterial, venous, otic, sublingual, dermal, epidermal, subdermal, implant, buccal, bioadhesive, mucosal and other similar environments. Likewise, it may be used in aquariums, industrial warehouses, laboratory facilities, hospitals, chemical reactions and other facilities.
Other features, advantages and embodiments of the invention will become apparent to those of ordinary skill in the art by the following description, accompanying examples and appended claims.